Tetrahydropyranylethers of steroids and process for their manufacture

ABSTRACT

TETRAHYDROPYRANYL ETHERS OF STEROIDS HAVING GESTAGENIC, ANTIPHLOGISTIC, ANOBOLIC, OR ANDROGENIC ACTION, SAID ETHERS BEING OF THE FORMULA   2-ST-O-,5-R2,6-X-OOC-,6-R1-TETRAHYDROPYRAN   WHEREIN R1 IS HYDROGEN OR LOWER ALKYL; R2 IS HYDROGEN, ALKYL OR ALKENYL; AND X IS HYDROGEN, ALKYL, ALKENYL, ARYL, ARALKYL, OR A CATION; AND ST IS A RADICAL OF AN ANDROSTANE, ANDROSTENE, PREGNANE, PREGNENE, OR PREGNADIENE, OR A HALO-DERIVATIVE THEREOF, OF OF A CARDENOLIDE OR BUFADIENOLIDE.

United States Patent 3,598,816 TETRAHYDROPYRANYLETHERS 0F STEROIDS ANDPROCESS FOR THEIR MANUFACTURE Werner Haede, Hofheim, Taunus, WernerFritsch, Neuenhain, Taunus, and Ulrich Stache, Gerhard Vogel, Hofheim,Taunus, and Kurt Radscheit, Kelkheim, Taunus, Germany, assignors toFarbwerke Hoechst Aktiengesellschaft vorrnals Meister Lucius andBruning, Frankfurt am Main, Germany No Drawing. Filed Sept. 13, 1967,Ser. No. 667,368 Claims priority, application Germany, Oct. 13, 1966,

F 50,421; Apr. 29, 1967, F 52,300 Int. Cl. C07c 173/00 US. Cl. 260-23955Claims ABSTRACT OF THE DISCLOSURE Tetrahydropyranyl ethers of steroidshaving gestagenic, antiphlogistic, anabolic, or androgenic action, saidethers being of the formula wherein R is hydrogen or lower alkyl; R ishydrogen, alkyl or alkenyl; and X is hydrogen, alkyl, alkenyl, aryl,aralkyl, or a cation; and St is a radical of an androstane, androstene,pregnane, pregnene, or pregnadiene, or of a halo-derivative thereof, orof a cardenolide or bufadienolide.

The present invention relates to tetrahydropyranylethers of steroids ofthe General Formula I St-O COOX in which St represents a steroidradical, R represents H or lower alkyl; R represents H, alkyl, oralkenyl; and X represents H, alkyl, aryl, aralkyl, or a cation. Toprepare the ethers, steroids carrying hydroxyl groups capable of beingesterified are reacted with dihydropyrane derivatives of the GeneralFormula II in which R and R have the meaning given above, and Rrepresents an alkyl, aryl or aralkyl radical, in the presence of an acidcatalyst and, if desired, the tetrahydropyranyl ether formed ishydrolyzed in an alkaline medium. If R represents a hydrogen atom or analkyl radical and R a benzyl radical, the benzyl radical is split off bycatalytic hydrogenation. If desired, the acid obtained can be convertedinto its salt with an equivalent amount of a base.

For the reaction, all steroids carrying hydroxyl groups capable of beingesterified are suitable. The hydroxyl groups may be in 3, 5, 6, 12, 14,15, 16, 17 or 21-position. Even several hydroxyl groups can be reacted.

Furthermore, even in steroids carrying several hydroxyl groups which aredistinguished by a graduated reactivity, only one hydroxyl group can bereacted by proper choice of the reaction conditions. For example 3- or21-hydroxyl groups can be reacted preferably, without considerablereaction of the 170w or lip-hydroxyl group, if the dihy- "ice dropyranecarboxylic acid ester quantity calculated for each hydroxyl group whichis to react is used and working is carried out under mild conditions,for example by using small quantities of a catalyst and by Working atlow temperatures.

Alcohols of the following steroids can be used as reagents, for example:androstane; androstene; pregnane; and pregnadiene; as well as the 4-,6-, or 9-halogen derivatives of these compounds. They are used,preferably: A4- androstene-l7B-ol-3-one, A4 pregnene-Zl-ol3,20-dione; A4pregnene 11,8, 17a, 21-triol-3,20-dione, A1,4pregnadiene-llfl- 17a,21-triol-3,20-dione, androstane-17/3-ol 3-one, A-androstene-3fi-ol-17-0ne, pregnane-3-ol-20-one, A-pregnene-35-ol-20-one or A -pregnadiene-3/3-ol-20- one, and furthermore4-, 5-, 6- or 9-halogen derivatives of the mentioned compounds as wellas their 6- or 16 alkyland 6- or 16-methylene derivatives. Furthermore,hydroxycardenolides and hydroxybufadienolides can be used.

For the variation of the process involving splitting off of the benzylradical by catalytic hydrogenation, only those unsaturated steroids canbe used as starting substances which do not contain a conjugated doublebond in the steroid structure.

The dihydropyrane derivatives used have been prepared according to I.Am. Chem. Soc. 73, 5270 (1951) or analogous procedures. The reactionbetween the steroid alcohol and the dihydropyrane derivative is carriedout suitably at low temperature, e.g. at about 0 C. to 40 C. Preferably,Working is carried out at room temperature. The reaction time liesbetween 1 hour and several days and depends on the reactivity of thesteroid hydroxyl groups which are to be esterified. Preferably, reactionis carried out in the presence of solvents. As such solvents, inertorganic solvents, suitably ethers, in particular cyclical ethers such astetrahydrofurane or dioxane, are used. For example dimethylformamide ordimethylsulfoxide can also be used.

As acid catalysts, acids can be used, preferably strong acids such asp-toluene sulfonic acid, hydrochloric acid or sulfuric acid.Furthermore, acid halides, in particular halides of phosphorus orsulfur, such as phosphorus oxychloride for example, can be used.

Working up of the reaction mixture is carried out by adding a base suchas pyridine diluted with Water. The tetrahydropyranylether formed isfiltered if the reaction has been carried out in a solvent which can bemixed with water. Otherwise, the reaction mixture is preferablyseparated and the solvent is evaporated under reduced pressure. Thereaction mixture can also be added directly into alkali-containing waterand the aqueous solution can be worked up as described above.

In order to obtain the free acid (Formula I:X=H), the ester formed ishydrolyzed for example with alkali, and the acid obtained from theaqueous solution of its alkali metal salt is isolated by adding organicacids such as acetic acid or formic acid or dilute mineral acids such ashydrochloric acid or sulfuric acid.

For splitting ofi benzyl by hydrogenation if R, represents a benzylradical, metals of the 8th group of the Periodic System, preferablypalladium, can be used as catalysts.

As solvents, the inert organic solvents usually employed forhydrogenation, or mixtures thereof, can be used, such as low molecularweight alcohols, especially ethanol or isopropanol, or ethers such asdiethylethe'r, tetrahydrofurane or dioxane.

The reaction conditions are those which are usual for hydrogenation. Theprocess is suitably performed at normal pressure and at lowtemperatures, between about 0 .and 50 C., preferably at roomtemperature.

If the molecule contains other sites which can undergo hydrogenation, itis suitable to use only a molar equivalent of hydrogen referred to thestarting substance. This is rapidly absorbed. The reaction perioddepends on the amount of catalyst used and amounts generally to betweensome minutes and some hours.

For the preparation of aqueous solutions of salts of the acids obtained,for which preferably alkali metal salts (such as Na or K) but alsoalkaline-earth salts or ammonium salts can be used, equivalent amountsof bases in aqueous solution are added to the acid. The solution has agood stability at pH between 8 and 12.

The products of the process can be used as such or in the form of theircorresponding salts with bases in admixture with pharmaceuticallysuitable carriers. The mode of application may be parenteral, oral or,in the form of ointments, also external. When parenterally applied,aqueous solution can be administered subcutaneously or intramuscularly.In ointments, the carriers usual for ointments are used.

The products of the present invention are, corresponding to nature ofthe steroid radical, pharmaceutically most important compounds withvaluable properties such as gestagenic, antiphlogostic, anabolic orandrogenic action. For example the alkali metal salts (X=Na or K), inaddition to their pharmacological properties which depend on the natureof the steroid radical, are distinguished by excellent water-solubilityand stability of their aqueous solutions in the neutral and alkalinerange. The esters (X=alkyl, aryl or aralkyl radical) are distinguishedby an increased solubility in oil.

The following examples serve to illustrate the invention but they arenot intended to limit it.

EXAMPLE 1 Tetrahydro-6'-(A1,4-pregnadiene-11,6, 17oz, did-3,20- dione-2l-oxy) -pyrane-2'-methyl-2'-carboxylic acid 5 grams of A1,4-pregnadiene-11B, 170:, 21-triol-3,20-dione are suspended in grams oftetrahydrofurane. 0015 cc. of phosphorus oxychloride is added to thissuspension while excluding moisture and stirring. Then 2.3 of2-carbomethoxy2-methyl-3,4-dihydro-2H pyrane (prepared according to J.Am. Chem. Soc. 73, 5270 (1951)), are added dropwise within 5 hours whilecontinuously stirring. During this process the steroid is dissolving.Then one drop of pyridine is added and the reaction mixture is pouredinto 100 cc. of 1 N soda solution. In this process part of thetetrahydropyranylether formed precipitates. The precipitation iscompleted by evaporating the tetrahydrofurane under reduced pressure ata bath temperature of C. The amorphous precipitate can be filtered withsuction. After washing with water and drying in a vacuum desiccator 7grams of the pyranylether are obtained. For the preparation of the freeacid, the 7 grams obtained are boiled in cc. of methanol with 20 cc. ofa 2 N solution of caustic soda for 6 hours under reflux. Then 100 cc. ofwater are added and the methanol is evaporated under reduced pressure.The clear aqueous solution is allowed to cool and acidified with 2 Nhydrochloric acid. During this process the carboxylic acid precipitates.After filtration, washing with water and drying in a vacuum desiccator 5grams are obtained (melting point -124 C.).

EXAMPLE 2 Tetrahydro 6' (Ga-methyI-A1.4-pregnadiene-l1p,171xdiol-3,20-dioue-21-oxy) pyrane 2' methyl 2' carboxylic acid 30 gramsof 6u-methyl-A1,4-pregnadiene-11,8, 17a, 21- tri0l-3,20-dione aresuspended in cc. of tetrahydrofurane and, after addition of 0.1 cc. ofphosphorus oxy- 4 ample 1. 31.5 grams of carboxylic acid are obtained asan amorphous precipitate. For the preparation of the sodium salt the31.5 grams obtained are dissolved in 200 cc. of water with 68 cc. ofcaustic soda solution and lyophilized. 33 grams of sodium salt areobtained (melting point 220 C. with decomposition).

EXAMPLE 3 Tetrohydro-6-(A4-pregnene-3,20-dione-17a-oxy)pyrane-2'-methyl-2'-carboxylic acid 1 grain ofA4-pregnene-17a-ol-3,20-dione is stirred for 90 hours with 1 cc. of2-carbomethoxy-2-methyl-3,4-dihydrO-ZH-pyrane and 0.01 cc. of phosphorusoxychloride in 5 cc. of tetrahydrofurane. Further treatment is carriedout analogous to Example 2. 0.45 gram of carboxylic acid is obtained(melting point 135 C.). (IR-maxima at 1650, 1700, 1730 and 2940 cmfEXAMPLE 4 Tetrahydro-6- (A4-androstene-3-one- 17 fi-oxy) -pyrane-2'-methyl-2'-carboxylic acid 1 gram of M-androstene-17,3-ol-3-one isstirred for 5 hours with 0.01 cc. of phosphorus oxychloride and 0.65 cc.of 2-carbomethoxy-2-methyl-3,4-dihydro-2H-pyrane in 4 cc. oftetrahydrofurane. Further treatment is carried out analogous to Example2. 1.4 grams of carboxylic acid are obtained (melting point 100-104 C.).(IR-maxima at 1650, 1670, 1730 and 2940 cmf EXAMPLE 5Tetrahydro-6-(AS-pregnene-ZO-one-3B-oxy)-pyrane-2- :methyl-2-carboxylicacid methyl ester 2 grams of A5-pregene-3fi-ol-20-one are stirred for 5hours at room temperature with 0.02 cc. of phosphoroxy chloride and 1.3cc. of Z-carbomethoxy-Z-methyl-3,4-dihydro-2H-pyrane in 8 cc. oftetrahydrofurane. The solution which has formed during this process ispoured into 100 cc. of water containing a few drops of soda solution.The crude ester product (Formula I: X:CH precipitates in crystallineform. 3 grams are obtained (melting point 100-110 C. (IR-maxima at 1145,1700, 1730 and 2935 cmr EXAMPLE 6 Tetrahydro 6' (Al,4-pregnadiene-113-17a-diol-3,20-dione-21-oxy) pyrane 3' (B-methylvinyl) 2 carboxylicacid methyl ester 2 carbomethoxy 3-(,B-methylvinyl)-3,4-dihydro-2H-pyrane is prepared as follows: 84 grams of acrolein and 126 grams ofsorbic acid methyl ester are heated for 2 hours to 190 C. in a vibratingautoclave with 3 grams of hydroquinone under 5 atmospheres of nitrogen.Then the reaction mixtures is distilled off (boiling at 150 C. under apressure of 30 mm. of mercury (115 g.).

3 cc. of this dihydropyrane derivative are stirred for 3 days with 5grams of Al,4-pregnadiene-l1fi,l7a,2l-triol- 3.20-dione and 0.025 cc. ofphosphoroxy chloride in 15 cc. of tetrahydrofurane. The reactionsolution is poured into 100 cc. of water containing 5 cc. of 2 N sodasolution after filtration of the steroid which has not reacted. Theamorphous precipitate which forms is filtered, washed with water anddried in high vacuum. The yield amounts to 4.6 grams. The freecarboxylic acid is obtained by hydrolysis as described in Example 2(melting point -190 C.).

EXAMPLE 7 Tetrahydro 6'(6a-9a-difluoro-16a-methyl-A1,4-pregnadiene-l1(3-17a-diol-3,20-dione-2l-oxy)pyrane 2'- methyl-2'-carboxylic acid methyl ester 100 mg. of6u,9u-difluoro-16a-methyl-A1,4-pregnadiene-llp, 17oz,2l-triol-3,20-dione are suspended in 1 cc. of tetrahydrofurane. To thissuspension 0.0415 cc. of 2- carbomethoXy-2-methyl-3.4-dihydro-2H-pyrane(prepared according to J. Am. Chem. Soc. 73, 5270 (1951) and 0.005

cc. of phosphorus oxychloride are added while stirring and under anitrogen atmosphere. While stirring, the suspension dissolves afterabout half an hour. The reaction mixture is left standing for two hoursat room temperature and then 10 cc. of ice Water and 0.5 cc. of 2 Nsodium carbonate solution are added. The tetrahydropyranyl ether whichhas formed precipitates in amorphous form. The precipitate is dissolvedin ether, the solvent is evaporated and the ether residue is heated to80 C. at 0.1 mm. of Hg.

Yield: 135 mg. (IR-maxima at 1060, 1130, 1620, 1650, 1720, 2940, and3460 cmf UV: emax, 237: 18400).

EXAMPLE 8 Tetrahydro 6' (6a-methyl-9a-fluoro-A1,4-pregnadiene-11B,17a-diol-3,20-dione 21-oxy) pyrane 2 methylcarboxylic acid methylester 200 mg. of 6a-methyl-9a-fluoro-A1,4-pregnadiene-11,3, 17a,21-triol-3,20-dione are suspended in 2 cc. of tetrahydrofuraue and 0.12cc. of 2-carbomethoxy-2-methyl-3,4- dihydro-ZH-pyrane (preparedaccording to J. Am. Chem. Soc. 73, 5270 (1951) and 0.006 cc. ofphosphorus oxychloride are added. The whole is stirred for 2 hours atroom temperature. After working up as described in Example 7, there areobtained 270 mg. of the above-described tetrahydropyranylether(IR-maxima at 1060, 1125, 1610, 1655, 1720, 2940 and 3460 cm.- UV: emax.238: 15000).

EXAMPLE 9 (a) Tetrahydro 6' (Am,,8-B[B,14fi-androstane-14B- 01- 17B-yl]butenolide 3f! oxy) pyrane 2' methyl-2-carboxylic acid methyl ester The2-carbobenZyloxy-2-methyl-3,4-dihydro-2H-pyrane used as startingmaterial is prepared as follows: 56 g. of acrolein and 100 g. ofmethacrylic acid benzyl ester are heated to 180 C. for 2 hours with 1.5g. of hydroquinone under a nitrogen pressure of 20 atmospheres and thewhole is then distilled. Boiling point: 108-110 C. under a pressure of0.05 mm. of mercury.

To 275 mg. of this dihydropyrane derivative, 400 mg. of digitoxigeninein 4 cc. of tetrahydrofurane are added together with 0.01 cc. ofphosphorus oxychloride and the whole is stirred for 4 hours at roomtemperature. Then cc. of ether are added and the reaction mixture is extracted with dilute soda solution. The ethereal layer is separated,dried with sodium sulfate, filtered and concentrated. The residue isdigested with water and filtered off. There is obtained an amorphousproduct melting at 48- 53 C.

IRmaxima at 1015, 1060, 1140, 1440, 1610, 1725, 1775, 2930 and 3470 cm.-

6 (b) Tetrahydro 6' (A055 ,B[5fi,14fi androstane- 14B ol 17,8 yl]butenolide 3,8 oxy) pyrane 2- methyl-2'-carboxylic acid 450 mg. oftetrahydro 6'-(Aa,B-,B[55,14fl-androstane-14;3-ol-17,8-yl]-butenolide-3/8-oxy) pyrane- -methyl-2'- carboxylic acidbenzyl ester are hydrogenated under normal pressure at room temperaturein 20 cc. of dioxane in the presence of 0.45 g. of palladium black.

After filtration of the catalyst a solution of mg. of sodium bicarbonatein 2 cc. of water is added and the solution is concentrated underreduced pressure in a rotation evaporator and extracted with ether. Theaqueous solution is acidified with dilute hydrochloric acid whereby theacid product precipitates. It is filtered off with suction and dried ina desiccator. Melting point: -80" C.

(IR-maxima at 1015, 1060, 1140, 1440, 1610, 1725, 1775, 2930 and 3470cmf What We claim is:

1. Tetrahydro 6' (A1,4-pregr1adiene-1 lfl-17a-dio1-3,20-dione-21-oxy)-pyrane-2-methyl-2'-carboxylic acid.

2. Tetrahydro 6 (6a-methyl-A1,4-pregnadiene-11,6, 17oz diol 3,20dione-21-oxy)-pyrane-2'-methy1-2'-carboxylic acid.

3. Tetrahydro 6 (A4-pregnene-3,20-dione-17a-oxy)-pyrane-2'-methyl-2-carboxylic acid.

4. Tetrahydro 6' (A4-audrostene-3-one-17B-oxy)-pyrane-2'-methyl-2'-carboxylic acid.

5. Tetrahydro 6'(A5-pregnene-20-one-318-oxy)-pyrane-2-methyl-2'-carboxylic acid methylester.

6. Tetrahydro 6' (A1,4-pregnadiene-11,8,17u-diol-3, 20-dione-21-oxy)pyrane 3' (fimethylvinyl)-2-carboxylic acid methyl ester.

7. Tetrahydro 6' (611,90: difluoro-16a-methyl-AL4- pregnadiene11,3,17u-diol-3,20-dione-2l-oxy)-pyrane-2- methyl-2-carboxylic acidmethyl ester.

8. Tetrahydro 6 (6u-methyl-9a-fluoro-A1,4-pregnadiene 11,13,170: diol3,20 dione 21 oxy) pyrane- 2-methyl-carboxylic acid methyl ester.

9. Tetrahydro 6' (Aa,/8-;8[5B,14,8-androstane-14fi-ol-17,B-yl]-butenolide-3;8-oxy) pyrane 2' methyl 2'- carboxylic acid methylester.

10. Tetrahydro 6' (Aa,,8}8[55,14fl-androstane-14B- ol yl] butenolide 3Boxy) pyrane 2' methyl- 2-carboxylic acid.

References Cited Dyerassi, Steroid Reactions, Holden-Day, Inc., SanFrancisco (1963), pp. 76 and 79 relied on.

ELBERT L. ROBERTS, Primary Examiner U.S. Cl. X.R. 260-23957

